New improved antibiotics are continually in demand, for the treatment of diseases in man. According to the World Health Organization, more than 95% of the Staphylococcus aureus isolates worldwide are now resistant to penicillin and up to 60% are resistant to methicillin (Breithaupt, H. Nat. Biotechnol. 17(12), 1165-9 (1999) and the references therein). Resistance is spreading from hospital-acquired infections to community-acquired pathogens, such as pneumococci and tuberculosis.
Penicillins and cephalosporins are the most frequently and widely used β-lactam antibiotics in the clinic. However, the development of resistance to β-lactam antibiotics by different pathogens has had a damaging effect on maintaining the effective treatment of bacterial infections. (Coleman, K. Expert Opin. Invest. Drugs 1995, 4, 693; Sutherland, R. Infection 1995, 23 (4) 191; Bush, K, Cur. Pharm. Design 1999, 5, 839-845) The most significant known mechanism related to the development of bacterial resistance to the β-lactam antibiotics is the production of class-A, class-B and class-C serine β-lactamases. These enzymes degrade the β-lactam antibiotics, resulting in the loss of antibacterial activity. Class-A enzymes preferentially hydrolyze penicillins where as Class-C lactamases have a substrate profile favoring cephalosporin hydrolysis. (Bush, K.; Jacoby, G. A.; Medeiros, A. A. Antimicrob. Agents Chemother. 1995, 39, 1211). To date over 250 different β-lactamases have been reported (Payne, D. J,: Du, W and Bateson, J. H. Exp. Opin. Invest. Drugs 2000, 247.) and there is a need for a new generation of broad spectrum β-lactamase inhibitors. Bacterial resistance to these antibiotics could be greatly reduced by administering the β-lactam antibiotic in combination with a compound which inhibits these enzymes. Accordingly, there is an ongoing need to discover new methods for the preparation of β-lactamase inhibitors.
The present invention satisfies the need for new processes for the preparation of β-lactamase inhibitors wherein said processes also provide advantages.